Unmet Need Justifies Risks For Pediatric Use Of Antipsychotics, FDA Advisory Committee Says

Panel’s votes on the safety of AstraZeneca’s Seroquel, Lilly’s Zyprexa and Pfizer’s Geodon to treat pediatric schizophrenia and bipolar disorder indicate that the severity of the conditions and need for additional treatments justify the known risks.

An FDA advisory panel June 9 endorsed the efficacy and safety of all three antipsychotic drugs under review for treating pediatric patients with schizophrenia and bipolar disorder.

The agency's Psychopharmacologic Drugs Advisory Committee discussed three applications over the two-day meeting - Lilly's Zyprexa (olanzapine), AstraZeneca's Seroquel (quetiapine) and Pfizer's Geodon ziprasidone) -all of which are approved for schizophrenia and bipolar disorder in adults.

In contrast to typical advisory committee agendas, FDA officials gave no presentation of data on any of the sNDAs discussed, saying they believed the drugs had demonstrated efficacy in the younger populations and that they believed the data would be fairly presented by the companies. Additionally, the agency concluded that in general, the safety profiles for the drugs in pediatric populations appear to be qualitatively similar to those seen in adults.

Asked why the applications were brought to the panel for review, FDA officials said at a press conference following the meeting that the controversial nature of the use and safety profiles of antipsychotic drugs merited the public discussion.

If approved, the drugs would join Johnson & Johnson's Risperdal (risperidone) and Bristol-Myers Squibb/Otsuka Pharmaceuticals' Abilify (aripiprazole) in carrying specific approvals for pediatric patients.

The atypical antipsychotics are known to be associated with acute extrapyramidal symptoms (EPS) and elevation of prolactin, as well as a risk of tardive dyskinesia (TD) that is not fully understood. Agency officials noted that with the exception of TD, all the risks occur quickly after starting the drug and involve relatively easy monitoring.

There was general agreement that the known metabolic risks of all three drugs - including increases in weight, lipids and glucose - were offset by the need for treatment for the indications.

Panel member and endocrinologist Frank Greenway, Pennington Biomedical Research Center, said the psychiatric conditions were more concerning than the metabolic side effects. "One can treat most of these metabolic issues, and you can function in life with them," he said. "Trying to balance the overall problems that you have with bipolar disorder and schizophrenia against some metabolic problems that are recognizable and treatable ... makes me think this is reasonable trade off."

Zyprexa's safety profile - which carries the most significant pediatric metabolic risk of the drugs presented - did not stand in the way of positive committee recommendations (¹ ).

They endorsed its efficacy for bipolar disorder with a vote of 17-0 and one abstention, and its safety profile with a vote of 11 to 4 with 3 abstentions. For schizophrenia, they voted 10-4 with 4 abstentions that olanzapine was efficacious and 11 to 5 with 2 abstentions that it was acceptably safe.

Though FDA stated in briefing documents released prior to the meeting stated that they were considering Zyprexa for second line use, the agency clarified that labeling would describe use as more of "one and a half line," meaning it would advise clinicians that given the risks associated with olanzapine, other medications should be considered first.

Perhaps the strongest committee endorsement was for AstraZeneca's Seroquel (quetiapine), proposed to treat acute bipolar mania in children and adolescents aged 10-17 years old and acute schizophrenia in adolescents aged 13 to 17 years old.

For schizophrenia, the panel voted 17-1 that Seroquel was efficacious and 16-0 with 2 abstentions that it was safe. For bipolar disorder, they voted 17 to 0 with one abstention that it was effective and 13-0 with 5 abstentions that it was acceptably safe.

Aiming for just one indication - acute manic or mixed episodes of bipolar I disorder in children and adolescents ages 10-17 years old - the committee voted 12-2 with 4 abstentions that Pfizer's Geodon (ziprasidone) was effective and 8-1 with 9 abstentions that it was safe.

Of note was the large number of abstentions, which Laughren said was probably due to the diversity of expertise present on the panel. In addition to psychiatrists, the committee included several cardiologists, an endocrinologist, and members from the Pediatric Advisory Committee and Risk Communication Advisory Committee.

Those that abstained cited concerns about a large number of subjects that were lost to follow up and insufficient data to answer safety questions in the younger populations.

The three drugs presented were studied in the acute setting, but FDA said there is agency precedent to extrapolate from adult data for indications for the maintenance treatment of pediatric patients. Laughren noted that it is ethically not feasibly to conduct the randomized withdrawal trial design necessary to evaluate a maintenance treatment claim in children.

- Jamie Hammon ([email protected])